Author Interviews, Genetic Research, Lipids, NEJM / 01.12.2016 Interview with: Brian A. Ference, M.D Division of Cardiovascular Medicine Wayne State University School of Medicine Detroit, MI What are the main findings? Response: Lifelong exposure to modestly lower plasma LDL-C levels caused by rare loss-of-function mutations in the PCSK9 gene is associated with a substantially lower lifetime risk of developing cardiovascular disease. This discovery motivated the development of monoclonal antibodies directed against PCSK9 which have now been shown to reduce plasma LDL-C levels by 50-60%. The cardiovascular medicine community is early anticipating the results of two large cardiovascular outcome trials that will determine if lowering LDL-C levels by inhibiting PCSK9 will reduce the risk of cardiovascular events. Because monoclonal antibodies and other therapies directed against PCSK9 are designed to recapitulate the phenotype of PCSK9 loss-of-function mutations, we reasoned that it may be possible to anticipate the efficacy and safety results of the ongoing cardiovascular outcome studies by more precisely characterizing the effect of genetic variants in the PCSK9 gene on the risk of both cardiovascular events and new onset diabetes. To do this, we a constructed genetic score consisting of multiple independently inherited variants in the PCK9 gene to create an instrument that mimics the effect of PCSK9 inhibitors. We then compared the effect of genetic variants that mimic the effect of PCSK9 inhibitors with the effect of genetic variants in the HMGCR gene that mimic the effect of statins to make inferences about the likely effect of PCSK9 inhibitors on the risk of cardiovascular events and new onset diabetes as compared to treatment with a statin. (more…)